The overall goal of this study is to examine whether depression or antidepressant medication use are positively associated with an increased risk of developing diabetes. In addition, we will explore possible mechanisms including depression and antidepressant medication use on body weight, insulin, fasting glucose, high-density lipoprotein (HDL), triglycerides, and inflammation markers. Postmenopausal women have an increasing prevalence of depression and diabetes and constitute a large percentage of the aging population in the United States. A meta-analysis of nine longitudinal studies found that depressed adults had a 37% increased risk of developing diabetes. This meta-analytic data conflicts with two recent studies, one demonstrated a positive association between any antidepressant use and diabetes risk, while elevated depression scores were not associated with diabetes risk;another study demonstrated that combined use of selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) was associated with a significantly increased risk of diabetes compared with TCA monotherapy. Additional analysis is necessary to examine whether depression itself or specific classes and combinations of antidepressant medication predicts a risk of developing diabetes. We will use data collected from the Women's Health Initiative (WHI) for this investigation. The WHI recruited general healthy postmenopausal women (N=161,808, 18% from ethnic minority groups) aged 50-79 at 40 clinical centers across the U.S from 1993-1998, and followed them until 2005. Antidepressant medication, depression and diabetes status were collected over 7 years of follow-up. The rates of retention and data collection completion were over 95% during the follow-up. At baseline, 15.8% of women had depression scores above the screening cutoff point for depression and 7.7% were taking antidepressant medications. During follow-up, the annual diabetes incidence was 0.64% and the cumulative incidence was 4.6%. The investigation between antidepressant use and diabetes risk have implications for new formulations of antidepressants and for women at heightened risk for diabetes. The methodology of this proposed study will involve several steps: 1) Creating analytical data sets;2) Testing study hypotheses based on the analyses of relationships between depression or antidepressant use and risk of developing diabetes;3) Testing study hypotheses based on the analyses of relationships of depression or antidepressant use with body weight and waist circumference;4) Testing study hypotheses based on the analyses of relationships between depression or antidepressant use and fasting glucose, insulin, HDL, triglycerides, and homeostasis model assessment of insulin resistance (HOMA-IR);5) Examination the association between depression or antidepressant use and levels of systemic inflammation markers;6) Testing whether risk of diabetes from depression or antidepressant medication use is mediated by body weight, waist circumference, fasting glucose, insulin, HOMA-IR, HDL cholesterol, triglycerides, and proinflammatory cytokines;and 7) Final report and manuscript preparation. PUBLIC HEALTH RELEVANCE: Project Narrative Postmenopausal women have an increasing prevalence of depression and diabetes and constitute a large percentage of the aging population in the United States. Using data collected from the Women's Health Initiative, we will investigate whether depression or antidepressant medication use are positively associated with an increased risk of developing diabetes. In addition, we will explore possible mechanisms. Approximately 11% of American women are taking antidepressant medication. The investigation between antidepressant use and diabetes risk have implications for new formulations of antidepressants and for women at heightened risk for diabetes.